During the past project period mechanisms of granulocyte- mediated tissue damage, particularly endothelial injury, have been investigated. Insights into atherogenesis and pulmonary vascular leak syndromes have been gained. The active involvement of granulocytes, particularly their adhesion and production of toxic oxygen species, has been analyzed, but the participation of endothelial cells in attracting, and stimulating, effector granulocytes has been largely ignored. The proposed studies will redress this chauvinism and explore changes in intrinsic adhesivity of endothelium after its perturbation by several agonists. First, the effects of endothelial exposure to model agonists including phorbol esters, calcium ionophore, toxic oxidants, and thrombin will be studied; special attention will be directed to altered exhibition/secretion of 3 potential adhesogens produced by cultured endothelium: namely, von Willebrand Factor, Platelet Activating Factor, and thrombospondin. In addition, correlations between increased endothelial adhesivity and increased cytosolic Ca++ and protein kinase C activity of endothelium will be sought. Second, previous interest in the possible role of herpes viruses in atherogenesis will be extended by proposed studies of effects of Herpes Simplex Virus (HSV) infections of endothelial monolayers; we shall particularly probe the role of HSV-induced neo-receptors for C3b and the Fc portion of immunoglobulin in attracting granulocytes with their associated cytotoxic potential. Third, effects on endothelial integrity of two inflammatory cell constituents which can be deposited on vascular walls will be examined; that is, lactoferrin from PMNs, and monocyte tumor necrosis factor have been implicated in vascular damage wrought by immune complexes and by endotoxin shock, respectively. Their effects on endothelial adhesivity will be studied. Following the aforementioned perturbations, endothelial cytotoxicity will be measured in vitro as well as in vivo using a rabbit skin edema model.